This invention was made with Government support under EY 03373 awarded by The National Eye Institute, and the Federal Government has limited rights therein.
This invention relates to a method and preparation for stimulating tear secretion. More particularly, it relates to the stimulation of tear secretion with topically applied melanocyte stimulating hormones which activate the melanotropin receptors of lacrimal gland tissue
There are a number of situations where it is desirable to increase the amount and/or to modify the nature of tear fluid produced by the eye. Illustrative instances include the treatment of a spectrum of dry eye disorders including, but not limited to, keratoconjunctivitis sicca, age-related dry eye, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, blepharitis, neurotrophic ocular surface disease and corneal exposure. In addition, patients who wear contact lenses may have sub-optimal rates of tear production for optimal contact lens wear. Increased tear production is likely to increase eye comfort and, contact lens comfort, and improve contact lens wear. These patients will therefore benefit from agents that could increase tear production.
The lacrimal gland is an exocrine gland that secretes protein, as well as, by different mechanisms, water and electrolytes. To stimulate secretion, agonists increase the intracellular free calcium concentration and/or the cyclic AMP level. However, protein is secreted by exocytosis, whereas electrolytes and water are secreted as the permeability of cell membranes is selectively increased to sodium, potassium and chloride. A given agonist could stimulate water and electrolyte secretion, but not protein secretion, and visa versa.
The topical administration of a vasoactive intestinal peptide stimulates lacrimal gland fluid secretion (Gilbard and Dartt, patent pending) and is known to increase cyclic AMP levels in lacrimal gland cells (Dartt et al, Am. J. Physio. 247: G502, 1984). The administration of adrenocorticotropic hormone as well as alpha melanocyte stimulating hormone (alpha-MSH) to tissue pieces in vitro has been shown to stimulate protein secretion. The data suggests that the actions of adrenocorticotropic hormone and of alpha-MSH are mediated by cAMP as a "second messenger." (Jahn et al Eur. J. Biochem 126: 623, 1982).
A topical mode of administration has several advantages. It eliminates the need for injections in patients with dry eye disorders, and thereby decreases untoward systemic effects, cost of therapy, and the amount of drug needed.
Accordingly, it is an object of this invention to provide an improved method for stimulating tear secretion by topical administration. It is another object of this invention to provide an improved method of stimulating lacrimal gland secretion by topical application of compounds to the ocular surface. It is also an object to provide an improved method for the treatment of dry eye disorders. Another object of the present invention is to facilitate the treatment of dry eye disorders by eliminating the need for systemic therapy such as injection. A further object is to provide an improved agent for topical application to improve eye comfort. It is another object of the present invention to provide an improved agent for topical application to enhance contact lens wear and comfort. A further object is to provide a method for increasing the amount of the tear fluid produced by lacrimal glad tissue. Other objects of the invention will in part be obvious and will in part appear hereinafter.